Immune Cell Modulation to Preserve Memory Phenotypes During Expansion
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing adoptive immunotherapies face challenges in maintaining and expanding desired immune cell subsets, such as T cells and NK cells, due to differentiation during expansion processes, leading to reduced proliferation and persistence, and there is a need for compositions and methods to improve therapeutic efficacy by enhancing the quality and quantity of these cells.
Innovation Solution
The use of specific compounds, including Dorsomorphin, Heptelidic acid, and GSK3 inhibitors, to modulate immune cells ex vivo, promoting proliferation, persistence, and increasing the ratio of desired cell subpopulations like naïve T cells, stem cell memory T cells, central memory T cells, and adaptive NK cells, through modulation of cell metabolism, signal transduction, and differentiation pathways.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If immune cells are activated and expanded during manufacturing, then cell quantity increases, but cell differentiation increases leading to reduced proliferation and persistence capacity
Solution Approach 1:
The patent applies parameter changes by modifying culture conditions including the use of specific cytokines (IL-2, IL-15, IL-21), small molecule inhibitors (mTOR inhibitors like rapamycin, PI3K inhibitors), and controlled stimulation protocols to maintain immune cells in a less differentiated state during expansion, thereby preserving their proliferative and persistent capabilities while achieving sufficient cell quantities
Solution Approach 2:
The patent employs preliminary action by pre-treating immune cells with specific agents before expansion to prevent differentiation. This includes pre-exposure to mTOR inhibitors, PI3K inhibitors, or other differentiation-blocking agents that prepare the cells for expansion while maintaining their stem-like or memory phenotypes, thus avoiding the differentiation that would otherwise occur during the expansion process
2Reliability
If T cell subsets are selected for therapeutic use, then anti-tumor activity is improved, but manufacturing complexity increases
Solution Approach 1:
The patent applies segmentation by dividing the manufacturing process into distinct stages: initial enrichment of desired T cell subsets (naive, central memory, or stem cell memory T cells) from patient samples, followed by controlled expansion using subset-specific culture conditions. This segmentation allows for targeted manipulation of each cell type's differentiation state, improving anti-tumor activity while managing manufacturing complexity through standardized protocols for each subset
Solution Approach 2:
The patent uses intermediary agents such as specific cytokines (IL-7 for naive T cell maintenance, IL-15 for memory T cell expansion), small molecule inhibitors, and engineered feeder cells as mediators to selectively expand and maintain desired T cell subsets. These intermediaries enable precise control over cell differentiation and proliferation, allowing manufacturers to enrich for therapeutically optimal subsets without requiring complex manual sorting or selection processes
Data Source
AI summary
Compounds that either produced a higher proportion or greater absolute number of phenotypically identified naïve, stem cell memory, central memory T cells, adaptive NK cells, and type I NKT cells are identified. Compositions and methods for modulating immune cells including T, NK, and NKT cells for adoptive cell therapies with improved efficacy are provided.